The title of this grant asks a question that most sleep researchers might think has been answered. Our paper and Mignot?s group?s paper, both appearing in September 2000, showed that human narcolepsy is linked to a loss of hypocretin/orexin (Hcrt) cells. We reported a 90% loss, with all narcoleptics having surviving cells, a finding that has been repeatedly replicated. We know that, whereas the animal models of narcolepsy are caused by genetic changes, the human disorder is not. HLA (human leukocyte antigen) linkage to narcolepsy suggests that it is an autoimmune disease. The HLA, DQB1*0602 genotype is present in 85-95% of human narcoleptics, but is also present in 20-30% of the general population. The incidence of narcolepsy is about 1 in 2,000. In most cases, identical twins living in the same household are discordant for narcolepsy. Various correlations, much weaker than the HLA relation, have been reported between human narcolepsy and T cell subtypes, antibodies to Tribbles, antibodies to the Hcrt receptor-2, strep infection and insect bites. But, despite many attempts, no one has convincingly shown that narcolepsy can be induced in animals by immune system manipulation. Recently, we and Scammell?s laboratory simultaneously reported a peculiar and massive increase in the number of detectable histamine (histidine decarboxylase) cells in human narcoleptics. This finding has important implications for the regulation of neurotransmitter expression and brain histamine function in general, and may provide an insight into other disorders where inflammation has been linked to pathology, such as Alzheimer?s and Parkinson?s. It also resonates with some earlier work we did showing greatly increased glial fibrillary acidic protein (GFAP), indicative of inflammation, in the histamine cell region of human narcoleptics. Although the peripheral role of histamine in inflammation is well understood, hence the widespread use of antihistamines, it is also known that histamine is involved in CNS inflammation and toxicity. Histamine opens the blood brain barrier. Furthermore Hcrt cells have been shown in in vitro studies to be much more likely to die from insult than adjacent hypothalamic cells. This suggests that the apparent selectivity of Hcrt cell loss that we and others have reported may be a reflection of the sensitivity of these cells to inflammation, rather than evidence for specific immunological targeting. We propose that the greatly increased number of histamine cells in human narcoleptics may mediate the destruction of Hcrt cells that causes narcolepsy. The mouse genetic work focusing on Hcrt may have discouraged a more comprehensive investigation of whether other regions of the brain are damaged or altered in human narcolepsy. We propose to investigate this hypothesis by looking for other evidence of damage explainable by histamine attack in narcoleptics. We will compare the damage present in human narcolepsy to that present in 4 animal genetic models of narcolepsy. We will further test the alternate ?compensatory hypothesis? by determining if other arousal related neuronal groups are increased in human narcoleptics. We are uniquely suited to do this study because we are in possession of the world?s largest collection of human narcoleptic brains (and matched controls) and because of our experience in working with these tissues as evidenced by our published results characterizing human narcolepsy.